AIIogeneic stem cell transplantation (SCT) is associated with high response rates in patients with hematologic malignancies, but the use of this therapeutic modality in patients with multiple myeloma has been limited by excessive toxicity. Previous studies have examined several approaches to reduce the toxicity of allogeneic SCT. These approaches have included T cell depletion of the donor marrow to reduce the incidence and severity of graft-vs-host disease (GVHD) and the development of a non-myeloablative preparative regimen to reduce treatment-related toxicities. Previous studies in this project have also examined the clinical role of allogeneic graft-vs-myeloma (GVM) immunity and have demonstrated the effectiveness of donor lymphocyte infusion (DLI) in the elimination of myeloma cells in vivo after allogeneic transplant. In these clinical trials, laboratory studies have demonstrated the profound immunologic effects of DLI and have begun to identify myeloma-associated antigens that play a potential role in the immunologic rejection of myeloma cells in vivo. Further clinical studies in this project will continue to develop safer methods to achieve consistent engraftment of allogeneic stem cells and infusion of donor CD4+ T cells to induce GVM. We will also characterize the antigenic targets of the GVM response and identify relevant myeloma tumor rejection antigens. Specific identification of the targets of GVM will lead to the development of new immune therapies to eliminate myeloma tumor cells after reconstitution of donor immunity. By both reducing the toxicity of allogeneic SCT and developing new methods to enhance GVM we will improve the outcome of patients undergoing allogeneic SCT. In conjunction with the development of new methods to augment autologous anti-myeloma immunity in Project by Munshi and approaches to target the microenvironment of tumor cells in Project by Anderson, we hope to achieve long-term disease free survival and potential cure in increasing numbers of patients with multiple myeloma. The studies proposed in Project by Ritz include 4 Specific Aims: 1. Evaluation of clinical approaches for enhancement of anti-myeloma immunity after allogeneic stem cell transplantation. 2. Serologic identification of myeloma antigens associated with tumor rejection. 3. Molecular analysis of allogeneic myeloma tumor-associated antigens. 4. Analysis of T cell responses to myeloma tumor antigens.